Letters to the Editor
To the Editors:
We read with interest the paper by Patterson et al1 on the variations of the unbound lopinavir/ritonavir (LPV/r) plasma concentrations according to trimesters of pregnancy. The authors address quite a relevant issue for clinicians, suggesting that the recommended LPV/r dose increase in the last trimesters2 may not be necessary (but for the patients harboring HIV-resistant strains), because the protein-unbound drug exposure is not modified in pregnant women. Some important concerns may however challenge this statement.
First, their study confirms that pregnancy is associated with a reduction of total LPV/r exposure and extends previous findings by documenting that the exposure of unbound LPV did not change significantly among trimesters, despite a 25% dose increase from week 30 of gestation. According to their interpretation, this would suggest that unbound LPV concentrations were not affected by pregnancy or dose. Conversely, we believe that the data reported in their paper provide a solid proof that pregnancy greatly impacts also on unbound LPV exposure as detailed below. First of all, a significant reduction in serum albumin concentrations has been observed in the gestational period compared with postpartum (from 3.1 to 4.4 g/dL). Such a reduction induces an increase in the unbound LPV fraction, which in turn is the only fraction that can be metabolized by hepatic enzymes. This is clearly documented by the great increase in the total and unbound LPV clearance (the pharmacokinetic parameter that takes into account the modification in drug dose) observed during pregnancy compared with postpartum. Indeed, as clearly shown in Table 2, the clearances of total LPV/r increased by 140%–200% during pregnancy, and this was associated with an increase in the unbound LPV/r clearances by 50%–140% versus postpartum. The fact that the exposure of unbound LPV/r (measured as area under the curve concentration) did not change significantly (from 1.6 to 1.8 µg·h·mL−1) during pregnancy was because of the 25% increase in the drug dose that compensates the increased drug clearance. In other words, it is likely that, if the authors did not increase LPV/r doses, pregnant women would have experienced a progressive increase in the LPV unbound drug fraction, a higher drug metabolism, and a reduction in the total drug exposure.
Second, the authors reported that <2% of all measured LPV concentrations were below the wild-type IC50 (50% inhibitory concentration), which for unbound LPV was fixed at 0.64 ng/mL. Such concentration seems to be too permissive compared with recent data by Acosta et al,3 which reported an IC50 for unbound LPV of 3.1 ng/mL, that is 5-fold higher compared with the IC50 considered by Patterson et al.1 Moreover, it must be underlined that the IC95 (95% inhibitory concentration) may more accurately reflect the antiretroviral drug concentration that is able to quantitatively inhibit in vitro HIV replication. Indeed, a concentration of 17 ng/mL has been reported as IC95 for unbound LPV, whereas the estimated protein binding–corrected IC95 (PBIC95) would be 168 ng/mL.3 Accordingly, it would be of interest to know how many samples collected in the study by Patterson et al1 were below the LPV IC95 concentration, a less permissive, more realistic, and, possibly, a more reliable cutoff.
In addition, the risk of HIV vertical transmission related to drug underexposure greatly overcomes the potential risk to experience LPV-related complications, mostly associated with LPV plasma levels exceeding 7000 ng/mL.4–6
Indeed, the extent to which plasma drug variations can be tolerated, without increasing the risk of toxicity or failure, is a complex issue and should take into account also the different scenarios of initial regimens (when HIV RNA levels may be very high) and switching options (with a full viral suppression).
Finally, some doubts may arise on the sample size required to adequately address this issue, as only 12 women are included in the study by Patterson et al. In addition, their serum albumin levels during pregnancy were relatively high (with nadir concentrations of 3.1 g/dL as shown in Table 1) compared with other experiences in pregnant women,7–9 reporting reduction in serum albumin levels ranging from 20% to 50%, with nadir albumin concentrations greatly <3.0 g/dL. This potential selection bias may be relevant because it has been shown that, when albumin concentrations dropped below this threshold, free drug clearance become really faster.10
We think that the data provided so far still support the LPV/r dose increase in the late phase of pregnancy as the more reliable and conservative recommendation.
1. Patterson KB, Dumond JB, Prince HA, et al.. Protein binding of lopinavir and ritonavir during 4 phases of pregnancy: implications for treatment guidelines. J Acquir Immune Defic Syndr. 2013;63:51–58.
2. Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States. Available at: http://aidsinfo.nih.gov/guidelines
. Accessed February 8, 2014.
3. Acosta EP, Limoli KL, Trinh L, et al.. Novel method to assess antiretroviral target trough concentrations using in vitro susceptibility data. Antimicrob Agents Chemother. 2012;56:5938–5945.
4. González de Requena D, Blanco F, Garcia-Benayas T, et al.. Correlation between lopinavir plasma levels and lipid abnormalities in patients taking lopinavir/ritonavir. AIDS Patient Care STDS. 2003;17:443–445.
5. Gutiérrez F, Padilla S, Navarro A, et al.. Lopinavir plasma concentrations and changes in lipid levels during salvage therapy with lopinavir/ritonavir-containing regimens. J Acquir Immune Defic Syndr. 2003;33:594–600.
6. Seminari E, Gentilini G, Galli L, et al.. Higher plasma lopinavir concentrations are associated with a moderate rise in cholestasis markers in HIV-infected patients. J Antimicrob Chemother. 2005;56:790–792.
7. Aweeka FT, Stek A, Best BM, et al.. Lopinavir protein binding in HIV-1-infected pregnant women. HIV Med. 2010;11:232–238.
8. Pavek P, Ceckova M, Staud F. Variation of drug kinetics in pregnancy. Curr Drug Metab. 2009;10:520–529.
9. Anderson GD. Pregnancy-induced changes in pharmacokinetics: a mechanistic-based approach. Clin Pharmacokinet. 2005;44:989–1008.
10. van Hest RM, Mathot RA, Pescovitz MD, et al.. Explaining variability in mycophenolic acid exposure to optimize mycophenolate mofetil dosing: a population pharmacokinetic meta-analysis of mycophenolic acid in renal transplant recipients. J Am Soc Nephrol. 2006;17:871–880.